ABCG2 impairs the activity of the aurora kinase inhibitor tozasertib but not of alisertib

Background: Recently, we have shown that the ATP-binding cassette (ABC) transporter ABCB1 interferes with the anti-cancer activity of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) but not of the aurora kina
Background: Recently, we have shown that the ATP-binding cassette (ABC) transporter ABCB1 interferes with the anti-cancer activity of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) but not of the aurora kinase A and B inhibitor alisertib (MLN8237). Preliminary data had suggested tozasertib also to be a substrate of the ABC transporter ABCG2, another ABC transporter potentially involved in cancer cell drug resistance. Here, we studied the effect of ABCG2 on the activity of tozasertib and alisertib.
Results: The tozasertib concentration that reduces cell viability by 50 % (IC50) was dramatically increased in ABCG2-transduced UKF-NB-3ABCG2 cells (48.8-fold) compared to UKF-NB-3 cells and vector-transduced control cells. The ABCG2 inhibitor WK-X-34 reduced tozasertib IC50 to the level of non-ABCG2-expressing UKF-NB-3 cells. Furthermore, ABCG2 depletion from UKF-NB-3ABCG2 cells using another lentiviral vector expressing an shRNA against the bicistronic mRNA of ABCG2 and eGFP largely re-sensitised these cells to tozasertib. In contrast, alisertib activity was not affected by ABCG2 expression.
Conclusions: Tozasertib but not alisertib activity is affected by ABCG2 expression. This should be considered within the design and analysis of experiments and clinical trials investigating these compounds.
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Metadaten
Author:Martin Michaelis, Florian Selt, Florian Rothweiler, Michael Wiese, Jindrich Cinatl
URN:urn:nbn:de:hebis:30:3-505722
DOI:http://dx.doi.org/10.1186/s13104-015-1405-4
ISSN:1756-0500
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=26415506
Parent Title (English):BMC Research Notes
Publisher:Biomed Central
Place of publication:London
Document Type:Article
Language:English
Year of Completion:2015
Date of first Publication:2015/09/28
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/07/25
Tag:ABCG2; Alisertib; Aurora kinase inhibitor; Drug resistance; MK-0457; MLN8237; Tozasertib; VX680
Volume:8
Issue:Art. 484
Pagenumber:5
First Page:1
Last Page:5
Note:
Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
HeBIS PPN:452197783
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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